ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity
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PROVIDER: PRJNA1159196 | ENA |
REPOSITORIES: ENA
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Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
2025-07-13 | GSE276835 | GEO
Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
2025-07-13 | GSE276834 | GEO
Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity (RNA)
| PRJNA1159200 | ENA
Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity (ChIP)
| PRJNA1159201 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-07-13 | GSE276836 | GEO
Project description:Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation
| PRJNA730564 | ENA
Project description:Eukaryotic gene expression requires factors that assist RNA polymerase in transcribing through nucleosomes. Human FACT complex (Facilitates chromatin transcription) was originally discovered as an important transcription elongation factor that modifies nucleosome structures and lowers the nucleosome energy barrier for Pol II passage. However, the mechanism by which FACT is recruited to transcribed regions is unknown. Here, we show that the Nucleosome Disassembly Factor (NDF)-mediated FACT phase separation is a key mechanism for FACT recruitment to these regions. In vitro, we found that NDF physically interacts with FACT and works synergistically to enhance Pol II transcription through nucleosomes. This interaction leads to the formation of gel-like NDF-FACT condensates under physiological conditions. Using single-molecule assays, we found that an NDF-FACT condensate forms right before Pol II approaches the nucleosome. The formation of these condensates not only increases local protein concentrations and retention time but also destabilizes nucleosomes. In human stem cells, NDF and FACT condensates are largely colocalized and have characteristics of liquid-liquid phase separation (LLPS). Moreover, cells expressing a single-point mutation in the NDF-FACT interaction domain, which disrupts the formation of NDF-FACT condensates, exhibit slower growth compared to wild-type cells, along with transcription defects and a reduced number of hSpt16 condensates and chromatin occupancy in the nucleus. Our data highlight the importance of phase separation in regulating gene expression and present a novel mechanism by which cellular factors work together to improve transcription efficiency on chromatin.
2025-08-05 | GSE300859 | GEO
Project description:Eukaryotic gene expression requires factors that assist RNA polymerase in transcribing through nucleosomes. Human FACT complex (Facilitates chromatin transcription) was originally discovered as an important transcription elongation factor that modifies nucleosome structures and lowers the nucleosome energy barrier for Pol II passage. However, the mechanism by which FACT is recruited to transcribed regions is unknown. Here, we show that the Nucleosome Disassembly Factor (NDF)-mediated FACT phase separation is a key mechanism for FACT recruitment to these regions. In vitro, we found that NDF physically interacts with FACT and works synergistically to enhance Pol II transcription through nucleosomes. This interaction leads to the formation of gel-like NDF-FACT condensates under physiological conditions. Using single-molecule assays, we found that an NDF-FACT condensate forms right before Pol II approaches the nucleosome. The formation of these condensates not only increases local protein concentrations and retention time but also destabilizes nucleosomes. In human stem cells, NDF and FACT condensates are largely colocalized and have characteristics of liquid-liquid phase separation (LLPS). Moreover, cells expressing a single-point mutation in the NDF-FACT interaction domain, which disrupts the formation of NDF-FACT condensates, exhibit slower growth compared to wild-type cells, along with transcription defects and a reduced number of hSpt16 condensates and chromatin occupancy in the nucleus. Our data highlight the importance of phase separation in regulating gene expression and present a novel mechanism by which cellular factors work together to improve transcription efficiency on chromatin.
2025-08-05 | GSE273680 | GEO
Project description:Eukaryotic gene expression requires factors that assist RNA polymerase in transcribing through nucleosomes. Human FACT complex (Facilitates chromatin transcription) was originally discovered as an important transcription elongation factor that modifies nucleosome structures and lowers the nucleosome energy barrier for Pol II passage. However, the mechanism by which FACT is recruited to transcribed regions is unknown. Here, we show that the Nucleosome Disassembly Factor (NDF)-mediated FACT phase separation is a key mechanism for FACT recruitment to these regions. In vitro, we found that NDF physically interacts with FACT and works synergistically to enhance Pol II transcription through nucleosomes. This interaction leads to the formation of gel-like NDF-FACT condensates under physiological conditions. Using single-molecule assays, we found that an NDF-FACT condensate forms right before Pol II approaches the nucleosome. The formation of these condensates not only increases local protein concentrations and retention time but also destabilizes nucleosomes. In human stem cells, NDF and FACT condensates are largely colocalized and have characteristics of liquid-liquid phase separation (LLPS). Moreover, cells expressing a single-point mutation in the NDF-FACT interaction domain, which disrupts the formation of NDF-FACT condensates, exhibit slower growth compared to wild-type cells, along with transcription defects and a reduced number of hSpt16 condensates and chromatin occupancy in the nucleus. Our data highlight the importance of phase separation in regulating gene expression and present a novel mechanism by which cellular factors work together to improve transcription efficiency on chromatin.
2025-08-05 | GSE273678 | GEO
Project description:Eukaryotic gene expression requires factors that assist RNA polymerase in transcribing through nucleosomes. Human FACT complex (Facilitates chromatin transcription) was originally discovered as an important transcription elongation factor that modifies nucleosome structures and lowers the nucleosome energy barrier for Pol II passage. However, the mechanism by which FACT is recruited to transcribed regions is unknown. Here, we show that the Nucleosome Disassembly Factor (NDF)-mediated FACT phase separation is a key mechanism for FACT recruitment to these regions. In vitro, we found that NDF physically interacts with FACT and works synergistically to enhance Pol II transcription through nucleosomes. This interaction leads to the formation of gel-like NDF-FACT condensates under physiological conditions. Using single-molecule assays, we found that an NDF-FACT condensate forms right before Pol II approaches the nucleosome. The formation of these condensates not only increases local protein concentrations and retention time but also destabilizes nucleosomes. In human stem cells, NDF and FACT condensates are largely colocalized and have characteristics of liquid-liquid phase separation (LLPS). Moreover, cells expressing a single-point mutation in the NDF-FACT interaction domain, which disrupts the formation of NDF-FACT condensates, exhibit slower growth compared to wild-type cells, along with transcription defects and a reduced number of hSpt16 condensates and chromatin occupancy in the nucleus. Our data highlight the importance of phase separation in regulating gene expression and present a novel mechanism by which cellular factors work together to improve transcription efficiency on chromatin.
2025-08-05 | GSE273681 | GEO